Fluorescence-Responsive Detection of Ag(I), Al(III), and Cr(III) Ions Using Cd(II) Based Pillared-Layer Frameworks.

Two Cd(II) based coordination polymers, {Cd3(btc)2(BTD-bpy)2]∙1.5MeOH∙4H2O}n (1) and [Cd2(1,4-ndc)2(BTD-bpy)2]n (2), where BTD-bpy = bis(pyridin-4-yl)benzothiadiazole, btc = benzene-1,3,5-tricarboxylate, and 1,4-ndc = naphthalene-1,4-dicarboxylate, were hydro(solvo)thermally synthesized. Compound 1 has a three-dimensional non-interpenetrating pillared-bilayer open framework with sufficient free voids of 25.1%, which is simplified to show a topological (4,6,8)-connected net with the point symbol of (324256)(344454628)(3442619728). Compound 2 has a three-dimensional two-fold interpenetrating bipillared-layer condense framework regarded as a 6-connected primitive cubic (pcu) net topology. Compounds 1 and 2 both exhibited good water stability and high thermal stability approaching 350 °C. Upon excitation, compounds 1 and 2 both emitted blue light fluorescence at 471 and 479 nm, respectively, in solid state and at 457 and 446 nm, respectively, in the suspension phase of H2O. Moreover, compounds 1 and 2 in the suspension phase of H2O both exhibited a fluorescence quenching effect in sensing Ag+, attributed to framework collapse, and a fluorescence enhancement response in sensing Al3+ and Cr3+, ascribed to weak ion-framework interactions, with high selectivity and sensitivity and low detection limit.

Penetrating glassy carbon neural electrode arrays for brain-machine interfaces.

This paper presents a fabrication method for glassy carbon neural electrode arrays that combines 3D printing and chemical pyrolysis technology. The carbon electrodes have excellent biological compatibility and can be used in neural signal recording. A pretreated Si wafer is used as the substrate for 3D printing, and then, stereolithography 3D printing technology is employed to print photosensitive resin into a cone shape. Next, chemical pyrolysis is applied to convert the 3D prints into glassy carbon electrodes and modify the electrochemical performance of the carbon electrodes. Finally, the glassy carbon electrodes are packed with conductive wires and PDMS. The proposed fabrication method simplifies the manufacturing process of carbon materials, and electrodes can be fabricated without the need of deep reactive ion etching (DRIE). The height of the carbon electrodes is 1.5 mm, and the exposure area of the tips is 0.78 mm2, which is convenient for the implantation procedure. The specific capacitance of the glassy carbon arrays is higher than that of a platinum electrode (9.18 mF/cm2 vs 3.32 mF/cm2, respectively), and the impedance at 1 kHz is lower (7.1 kΩ vs 8.8 kΩ). The carbon electrodes were tested in vivo, and they showed excellent performance in neural signal recording. The signal-to-noise ratio of the carbon electrodes is 50.73 ± 6.11, which is higher than that of the Pt electrode (20.15 ± 5.32) under the same testing conditions. The proposed fabrication method of glassy carbon electrodes provides a novel approach to manufacture penetrating electrodes for nerve interfaces in biomedical engineering and microelectromechanical systems.

Flexible 3D carbon nanotubes cuff electrodes as a peripheral nerve interface.

The cuff electrode provides a stable interface with peripheral nerves, which has been widely used in basic research and clinical practice. Currently, the cuff electrodes are limited by the planar processing of microfabrication. This paper presents a novel cuff electrode using high-aspect ratio carbon nanotubes (CNTs) integrated on a flexible biocompatible parylene. The microfabrication process unites the high quality vertical CNTs grown at high temperature with the heat sensitive parylene substrate in a highly controllable manner. The fabricated cuff electrodes have been utilized for extracellular nerve stimulation in rats. The experimental results demonstrate the proposed CNT electrode has a better performance than Pt electrode in nerve stimulation. Moreover, the effect of electrode position and stimulation frequency is demonstrated in this paper. This preliminary data indicates that flexible 3D CNTs cuff electrode provides an excellent platform for functional electrical stimulation.

Biosafety and chemical solubility studies of multiscale crystal-reinforced lithium disilicate glass-ceramics.

Lithium disilicate (Li2 Si2 O5 ) glass-ceramics are currently a more widely used all-ceramic restorative material due to their good mechanical properties and excellent aesthetic properties. However, they have a series of problems such as high brittleness and low fracture toughness, which has become the main bottleneck restricting its development. Therefore, in order to compensate for these shortcomings, we propose to prepare a reinforced glass-ceramics with better mechanical properties and to test the biosafety and chemical solubility of the material. Li2 Si2 O5 whiskers were synthesized by a one-step hydrothermal method, and multi-scale crystal-enhanced Li2 Si2 O5 glass-ceramics were prepared by reaction sintering. The biosafety of multi-scale crystal-reinforced Li2 Si2 O5 glass-ceramics was investigated by in vitro cytotoxicity test, rabbit pyrogen test, mice bone marrow micronucleus test, skin sensitization test, sub-chronic systemic toxicity test, and chronic systemic toxicity test. Additionally, the chemical solubility of multi-scale crystal-reinforced Li2 Si2 O5 glass-ceramics was investigated. The test results showed that the material was non-cytotoxic, non-thermogenic, non-mutagenic, non-sensitizing, and non-systemic. The chemical solubility, determined to be 377 ± 245 µg/cm2 , complied with the ISO 6872 standard for the maximum solubility of ceramic materials. Multi-scale crystal-reinforced Li2 Si2 O5 glass-ceramics' biosafety and chemical solubility met current normative criteria, and they can move on to mechanical property measurements (such as flexural strength test, fatigue life test, friction and wear property study, etc.) and bonding property optimization, which shows promise for future clinical applications.

Recent advances in composite hydrogels: synthesis, classification, and application in the treatment of bone defects.

Bone defects are often difficult to treat due to their complexity and specificity, and therefore pose a serious threat to human life and health. Currently, the clinical treatment of bone defects is mainly surgical. However, this treatment is often more harmful to patients and there is a potential risk of rejection and infection. Hydrogels have a unique three-dimensional structure that can accommodate a variety of materials, including particles, polymers and small molecules, making them ideal for treating bone defects. Therefore, emerging composite hydrogels are considered one of the most promising candidates for the treatment of bone defects. This review describes the use of different types of composite hydrogel in the treatment of bone defects. We present the basic concepts of hydrogels, different preparation techniques (including chemical and physical crosslinking), and the clinical requirements for hydrogels used to treat bone defects. In addition, a review of numerous promising designs of different types of hydrogel doped with different materials (e.g., nanoparticles, polymers, carbon materials, drugs, and active factors) is also highlighted. Finally, the current challenges and prospects of composite hydrogels for the treatment of bone defects are presented. This review will stimulate research efforts in this field and promote the application of new methods and innovative ideas in the clinical field of composite hydrogels.

Applications of Bacterial Cellulose-Based Composite Materials in Hard Tissue Regenerative Medicine.

BACKGROUND: Cartilage, bone, and teeth, as the three primary hard tissues in the human body, have a significant application value in maintaining physical and mental health. Since the development of bacterial cellulose-based composite materials with excellent biomechanical strength and good biocompatibility, bacterial cellulose-based composites have been widely studied in hard tissue regenerative medicine. This paper provides an overview of the advantages of bacterial cellulose-based for hard tissue regeneration and reviews the recent progress in the preparation and research of bacterial cellulose-based composites in maxillofacial cartilage, dentistry, and bone. METHOD: A systematic review was performed by searching the PubMed and Web of Science databases using selected keywords and Medical Subject Headings search terms. RESULTS: Ideal hard tissue regenerative medicine materials should be biocompatible, biodegradable, non-toxic, easy to use, and not burdensome to the human body; In addition, they should have good plasticity and processability and can be prepared into materials of different shapes; In addition, it should have good biological activity, promoting cell proliferation and regeneration. Bacterial cellulose materials have corresponding advantages and disadvantages due to their inherent properties. However, after being combined with other materials (natural/ synthetic materials) to form composite materials, they basically meet the requirements of hard tissue regenerative medicine materials. We believe that it is worth being widely promoted in clinical applications in the future. CONCLUSION: Bacterial cellulose-based composites hold great promise for clinical applications in hard tissue engineering. However, there are still several challenges that need to be addressed. Further research is needed to incorporate multiple disciplines and advance biological tissue engineering techniques. By enhancing the adhesion of materials to osteoblasts, providing cell stress stimulation through materials, and introducing controlled release systems into matrix materials, the practical application of bacterial cellulose-based composites in clinical settings will become more feasible in the near future.

Efficacy confirmation of Scutellaria baicalensis Georgi in the treatment of periodontitis via topical administration and active ingredients screening.

ETHNOPHARMACOLOGICAL RELEVANCE: Periodontal disease is a complex inflammatory disease that seriously affects peoples' lives. Scutellaria radix (SR) is traditionally used as a folk medicine to clear away heat and dampness, purge fire and detoxification. Although it has been extensively used as a medicinal plant to treat a variety of inflammatory illnesses, the efficacy and active ingredient for topical administration in the treatment of periodontitis is unknown. AIM OF STUDY: The aim of this study was to screen and validate the active ingredients in SR for the prevention and treatment of periodontitis. MATERIALS AND METHODS: A ligature-induced periodontitis in rats was used to investigate the efficacy of topical administration of SR for the treatment of periodontitis, and the active fraction was screened after separation of the aqueous extract of SR into fractions of different polarities using a lipopolysaccharide (LPS)-induced cell model. Chromatographic fingerprints were established for 18 batches of SR by high performance liquid chromatography. The potential active components were screened using spectral effect relationship analysis and the target cell extraction method. RESULTS: SR has good efficacy in the topical treatment of periodontitis, according to animal experiments. Five active ingredients were screened out and their anti-inflammatory activity was confirmed in vitro. CONCLUSION: The main active compounds in the treatment of periodontitis via topical administration of SR were found and this provides an experimental basis for further studies on the pharmacodynamic material basis of SR, as well as reference for the comprehensive evaluation of SR quality and the development of substitute resources.

Circadian Clock Regulation via Biomaterials for Nucleus Pulposus.

Circadian clock disorder during tissue degeneration has been considered the potential pathogenesis for various chronic diseases, such as intervertebral disc degeneration (IVDD). In this study, circadian clock-regulating biomaterials (ClockMPs) that can effectively activate the intrinsic circadian clock of nucleus pulposus cells (NPCs) in IVDD and improve the physiological function of NPCs for disc regeneration are fabricated via air-microfluidic technique and the chemical cross-linking between polyvinyl alcohol and modified-phenylboronic acid. In vitro experiments verified that ClockMPs can scavenge reactive oxygen species to maintain a stable microenvironment for the circadian clock by promoting the binding of BMAL1 and CLOCK proteins. ClockMPs can regulate the expression of core circadian clock genes by activating the PI3K-AKT pathway in NPCs to remodel the intrinsic circadian clock and promote extracellular matrix synthesis. Furthermore, in vivo experiments of IVDD treated with ClockMPs proved that ClockMPs can promote disc regeneration by regulating the circadian clock of NPCs. In conclusion, ClockMPs provided a novel and promising strategy for circadian clock regulation during tissue regeneration.

OIC-A006-loaded true bone ceramic heals rabbit critical-sized segmental radial defect.

It has been reported that OIC-A006, an osteogenically inducible compound, is able to promote osteogenesis in vitro and in vivo. In this study, we used a rabbit critical-sized segmental radial defect model (CSD) (15 mm) to analyse the osteogenic activity of OIC-A006 in non-cell-seeded tissue engineering bone substitutes. The scaffold carrier was bovine sintered bone "true bone ceramic (TBC)". OIC-A006 was delivered by PLGA (D,L-lactide-co-glycolide acid) microspheres. Drug-free PLGA microspheres and rhBMP-2-loaded PLGA microspheres were used as negative and positive control groups, respectively. Three kinds of composite were fabricated by coupling TBC, type-I collagen and the corresponding microspheres. The animals were randomly divided into 4 groups: (1) Group A: defect only, (2) group B:TBC/Collagen/drug-free-microspheres, (3) group C:TBC/Collagen/ OIC-A006-microspheres, (4) group D: TBC/Collagen/rhBMP-2-microspheres. The samples were analysed by histology, X-ray,microcomputed tomography (micro-CT), and biomechanical analyses. The results showed that OIC-A006 promoted bone regeneration to a remarkable extent. It is suggested that the application of OIC-A006 might be a valuable method in bone tissue engineering for healing large segmental defects of long bones. However, the biomechanical strength was a little inferior to that of BMPs.

NIR-PTT/ROS-Scavenging/Oxygen-Enriched Synergetic Therapy for Rheumatoid Arthritis by a pH-Responsive Hybrid CeO2-ZIF-8 Coated with Polydopamine.

Rheumatoid arthritis (RA) is an inflammatory type of arthritis that causes joint pain and damage. The inflammatory cell infiltration (e.g., M1 macrophages), the poor O2 supply at the joint, and the excess reactive oxygen species (ROS)-induced oxidative injury are the main causes of RA. We herein report a polydopamine (PDA)-coated CeO2-dopped zeolitic imidazolate framework-8 (ZIF-8) nanocomposite CeO2-ZIF-8@PDA (denoted as CZP) that can synergistically treat RA. Under near-infrared (NIR) light irradiation, PDA efficiently scavenges ROS and results in an increased temperature in the inflamed area because of its good light-to-heat conversion efficiency. The rise of temperature serves to obliterate hyper-proliferative inflammatory cells accumulated in the diseased area while vastly promoting the collapse of the acidic-responsive skeleton of ZIF-8 to release the encapsulated CeO2. The released CeO2 exerts its catalase-like activity to relieve hypoxia by generating oxygen via the decomposition of H2O2 highly expressed in the inflammatory sites. Thus, the constructed CZP composite can treat RA through NIR-photothermal/ROS-scavenging/oxygen-enriched combinative therapy and show good regression of pro-inflammatory cytokines and hypoxia-inducible factor-1α (HIF-1α) in vitro and promising therapeutic effect on RA in rat models. The multimodal nano-platform reported herein is expected to shed light on the design of synergistic therapeutic nanomedicine for effective RA therapy.

Cartilage regeneration of adipose-derived stem cells in a hybrid scaffold from fibrin-modified PLGA.

Adipose-derived stem cells (ASCs) appear to be a useful stem cell population, which has been shown to possess multipotentiality. The aim of this study was to evaluate the utility of ASCs in tissue-engineered cartilage using a hybrid scaffold from fibrin-modified PLGA scaffold. ASCs were isolated from rabbit adipose tissue. The PLGA scaffold was prepared by low-temperature deposition technology and the hybrid scaffold was fabricated by a freeze-drying method. When ASCs were seeded onto fibrin-modified PLGA scaffold in vitro, enhanced cellular viability was observed compared to unmodified PLGA scaffold. The analysis of proteoglycan and collagen II revealed that fibrin-modified scaffold succeeded in inducing ASCs to differentiate into chondrocytes in vitro. A preliminary study on cartilage regeneration was also performed in vivo. Observation of histology and immunoblotting demonstrated that ASCs containing the hybrid scaffold promoted cartilage regeneration in the defects of articular cartilage much better than other groups. These results indicated that ASCs containing the hybrid scaffold are a more effective way to potentially enhance articular cartilage regeneration.

Screening and analysis of cyclooxygenase-2 inhibitors from the complex matrix: A case study to illustrate the important effect of immobilized enzyme activity in magnetic ligand fishing.

Magnetic ligand fishing is one of the most widely used methods to screen and separate potentially bioactive compounds from complex mixtures. However, it is poorly understood the ambiguous relations between immobilized enzyme activity and fishing results (accuracy and sensitivity). Therefore, to investigate the underlying relationship of them, we fabricated the immobilized enzyme with different activities by introducing a novel support material, nickel ions (Ni2+) functionalized magnetic mesoporous silica microspheres (MMSM@PDA-Ni2+). It possesses a higher activity than the previous report because of site-directed immobilization. Then, the immobilized COX-2 with different activities were prepared using different immobilization methods, including Ni2+ affinity-oriented immobilization, polydopamine (PDA) covalent immobilization, and conventional glutaraldehyde (GA) covalent immobilization. A standard mixture (COX-2 inhibitors and noninhibitors) and green tea extract were used to compare and evaluate the fishing results systematically. It displayed the fished inhibitors were dramatically reduced with the decreased activity of immobilized COX-2, indicating that immobilized enzyme activity played a critical role in a reliable magnetic ligand fishing analysis. This development questions some of the previous studies aimed at rapid screening bioactive compounds in natural products and opens new possibilities for accurate and sensitive magnetic ligand fishing analysis. Also, the introduced novel materials with mild immobilization strategy preserve enzyme activity and spatial conformational, therefore, provides a valuable tool in future applications.

Vascularized 3D printed scaffolds for promoting bone regeneration.

3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality.

[Instant and fatigue stability analysis of anterior lumbar interbody fusion with stand-alone cage].

OBJECTIVE: To investigate the spinal segment instant and fatigue stability of anterior lumbar interbody fusion with stand-alone cage. METHODS: The vertebrae L4 and S1 of 6 human lumbar specimens (L3 - S1) were embedded with dental base acrylic resin powder and fixed on mechanical machine, and the L4/L5 and L5/S1 disk spaces were left active. The 6 specimens underwent mechanical test as control group first, and then used as experimental group with a cage implanted in L5/S1. Instant instability was tested in three directions: flexion, extension, and lateral bend. The relative movement of L4/L5 and L5/S1 was recorded. Fatigue instability was tested after 50 000 times of flexion-extension movement, and the relative displacement between the cage and S1 was recorded. RESULT: In the three directions of flexion, extension, and lateral bend, the relative movements of L5/S1 in the experimental group were 0. 83 +/- 0.26 degrees, 1.60 +/- 0.19 degrees, and 0.72 +/- 0.20 degrees respectively, all significantly decreased than those of the control group (3.60 +/- 0.30 degrees, 4.82 +/- 0.34 degrees, and 3.80 +/- 0.28 degrees respectively, all P < 0.01). The relative movement of L4/L5 of the experimental group were 5.82 +/- 0.36 degrees, 5.38 +/- 0.30 degrees, and 4.96 +/- 0.29 degrees in the three directions respectively, all significantly higher than those of the control group (4.16 +/- 0.33 degrees, 4.02 +/- 0.30 degrees, and 3.48 +/- 0.34 degrees respectively, all P <0.01). After 50 000 times of flexion-extension fatigue movement, the relative displacement between the cage and S1 was zero. CONCLUSION: Anterior lumbar interbody fusion with a stand-alone cage has excellent instant and fatigue stability, which can provide enough stability for clinical bone fusion without other internal fixation.

[Experimental study of core binding factor a1 gene-modified rabbit skin fibroblasts enhance bone defect repair].

OBJECTIVE: To investigate bone defect healing by true bone ceramic complex carrying core binding factor a1 (Cbfa1) gene modified rabbit skin fibroblasts. METHODS: Transfect rabbit skin fibroblasts (RSF) with both eukaryotic expression vector pSG5 which could express Cbfa1 gene and pSG5. After being cultured for 48 h, the transfected RSF were seeded into true bone ceramic (TBC) of 2 cm in length and 4 mm in diameter to construct pSG5-Cbfa1/RSF/TBC complex and pSG5/RSF/TBC complex. Forty-eight bone defect model rabbits were randomized into four groups, each has 6 rabbits (12 radius), due to different treatment. group I: with pSG5-Cbfa1/RSF/TBC complex, group II: with pSG5/RSF/TBC complex, group III: with TBC, Group IV: empty control. After being seeded and cultured for about 24 h the complexes were implanted into 2 cm long bone defects in the middle of bilateral radius of rabbits. The radius were inspected by X-ray and then the specimens were collected at the end of the fourth and twelfth weeks after operation. Then, the specimens were decalcified and histologically investigated with Hematoxylin eosin staining and Masson staining methods. Newly synthesized trabecular bone was inspected by image analysis system and the strength of bone defect area treated with graft-implantation was tested with biomechanical method-three point bending test. RESULTS: In group I, trabecular bone was actively synthesized to generate a great amount of trabecular bone and osteon. Preliminary union and bone defect healing were completed with good biomechanical characteristics. There were no newly synthesized trabecular in the other three groups, and bone defect healing were not discovered. The amount of newly synthesized trabecular bone and the results of biomechanical testing differed significantly between group I and the other three (P < 0.01). The efficacy of group I was significantly better than that of the other three groups. CONCLUSION: True bone ceramic complex composed with Cbfa1 gene modified rabbit skin fibroblasts can effectively heal bone defect in rabbits.

Influence of ultrafiltration membrane on ophiopogonins and homoisoflavonoids in Ophiopogon japonicus as measured by ultra-fast liquid chromatography coupled with ion trap time-of-flight mass spectrometry.

Ultrafiltration is one of the most fascinating technologies, which makes it possible to improve the quality of traditional medicines for application in the pharmaceutical industry. However, researchers have paid little attention to the effect of ultrafiltration membrane on traditional medicines chemical constituents. In this work, Ophiopogon japonicus (L.f) Ker-Gawl. was used as an example to illuminate the influence of ultrafiltration with different material and molecular weight cut-off (MWCO) membrane on natural chemical constituents as measured by ultra-fast liquid chromatography coupled with ion trap time-of-flight mass spectrometry (UFLC-IT-TOF/MS). Our results indicated that ultrafiltration membrane significantly impacted homoisoflavonoids, especially homoisoflavonoids that were almost completely retained on the polyethersulfone (PES) membrane. We also found that the larger number of aglycone hydroxy and sugar moiety in steroid saponins, the higher the transmittance. Furthermore, the passage rate (%) of ophiogenin type saponins was higher than that of others. The possible adsorptive mechanisms were hydrogen bonding, hydrophobic interactions, and benzene ring interaction by π-π stacking. In conclusion, it is crucial to choose appropriate ultrafiltration membrane based on the characteristics of produce products for application of ultrafiltration technique.

Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system.

As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are "shielded" by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment.

In Vivo Study of Hydroxyapatite-coated Hat Type Cervical Intervertebral Fusion Cage Combined With IGF-I and TGF-ß1 in the Goat Model.

STUDY DESIGN: An in vivo animal experimental study. OBJECTIVE: To investigate the hydroxyapatite (HA) coating in a modified fusion cage in improving the results of cervical intervertebral fusion and the role of combination of IGF-I and TGF-ß1 treatment in a goat cervical spine interbody fusion model. MATERIALS AND METHODS: Thirty-two goats were divided into 4 groups (n=8 for each) and underwent C3-4 discectomy and intervertebral fusion by the following methods: group 1, autologous tricortical iliac crest bone graft; group 2, cage only; group 3, cage coated with HA; group 4, cage coated with HA+IGF-I and TGF-ß1. Radiography was performed preoperatively, postoperatively, and after 1, 2, 4, 8, and 12 weeks. At the same time points, disk space height, intervertebral angle, and lordosis angle were measured. At 12 weeks postoperatively, the goats were killed and fused segments were harvested. Biomechanical study was performed in flexion, extension, axial rotation, and lateral bending with a nondestructive stiffness method to determine the range of motion and stiffness. All cervical fusion specimens underwent histomorphologic studies. RESULTS: All 3 cage-treated groups showed significantly higher values for disk space height, intervertebral angle, and lordosis angle compared with the autologous tricortical iliac group at 1, 2, 4, 8, and 12 weeks after surgery (P<0.05). The stiffness of hat-shaped cervical intervertebral fusion cage coated with HA+IGF-I and TGF-ß1 in flexion, extension, and lateral bending was significantly greater than that of the other groups (P<0.05), and the stiffness of hat-shaped cervical intervertebral fusion cage coated with HA in extension, axial rotation, and lateral bending was significantly greater than that of fusion with the bone graft and cage-only groups (P<0.05). Histomorphologic evaluation showed better fusion in 3 cage groups than in the bone graft group. In group 4 of the cage coated with HA+IGF-I and TGF-ß1, a slightly more advanced bone matrix formation was shown than in groups without coating. CONCLUSIONS: HA coating can improve the fusion effect of the cervical intervertebral cage, and IGF-I and TGF-ß1 can enhance bone fusion.

Desferrioxamine reduces ultrahigh-molecular-weight polyethylene-induced osteolysis by restraining inflammatory osteoclastogenesis via heme oxygenase-1.

As wear particles-induced osteolysis still remains the leading cause of early implant loosening in endoprosthetic surgery, and promotion of osteoclastogenesis by wear particles has been confirmed to be responsible for osteolysis. Therapeutic agents targeting osteoclasts formation are considered for the treatment of wear particles-induced osteolysis. In the present study, we demonstrated for the first time that desferrioxamine (DFO), a powerful iron chelator, could significantly alleviate osteolysis in an ultrahigh-molecular-weight polyethylene (UHMWPE) particles-induced mice calvaria osteolysis model. Furthermore, DFO attenuated calvaria osteolysis by restraining enhanced inflammatory osteoclastogenesis induced by UHMWPE particles. Consistent with the in vivo results, we found DFO was also able to inhibit osteoclastogenesis in a dose-dependent manner in vitro, as evidenced by reduction of osteoclasts formation and suppression of osteoclast specific genes expression. In addition, DFO dampened osteoclasts differentiation and formation at early stage but not at late stage. Mechanistically, the reduction of osteoclastogenesis by DFO was due to increased heme oxygenase-1 (HO-1) expression, as decreased osteoclasts formation induced by DFO was significantly restored after HO-1 was silenced by siRNA, while HO-1 agonist COPP treatment enhanced DFO-induced osteoclastogenesis inhibition. In addition, blocking of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway promoted DFO-induced HO-1 expression, implicating that p38 signaling pathway was involved in DFO-mediated HO-1 expression. Taken together, our results suggested that DFO inhibited UHMWPE particles-induced osteolysis by restraining inflammatory osteoclastogenesis through upregulation of HO-1 via p38MAPK pathway. Thus, DFO might be used as an innovative and safe therapeutic alternative for treating wear particles-induced aseptic loosening.

Deferoxamine released from poly(lactic-co-glycolic acid) promotes healing of osteoporotic bone defect via enhanced angiogenesis and osteogenesis.

The regeneration capacity of osteoporotic bones is generally lower than that of normal bones. Current methods of osteoporotic bone defect treatment are not always satisfactory. Recent studies demonstrate that activation of the hypoxia inducible factor-1α (HIF-1α) pathway, by genetic methods or hypoxia-mimicking agents, could accelerate bone regeneration. However, little is known as to whether modulating the HIF-1α pathway promotes osteoporotic defect healing. To address this problem in the present study, we first demonstrated that HIF-1α and vascular endothelial growth factor expression levels are lower in osteoporotic bones than in normal bones. Second, we loaded poly(Lactic-co-glycolic acid) (PLGA) with the hypoxia-mimetic agent deferoxamine (DFO). DFO released from PLGA had no significant effect on the proliferation of mesenchymal stem cells (MSCs); however, DFO did enhance the osteogenic differentiation of MSCs. In addition, DFO upregulated the mRNA expression levels of angiogenic factors in MSCs. Endothelial tubule formation assays demonstrate that DFO promoted angiogenesis in human umbilical vein endothelial cells. Third, untreated PLGA scaffolds (PLGA group) or DFO-containing PLGA (PLGA + DFO group) were implanted into critically sized osteoporotic femur defects in ovariectomized rats. After treatment periods of 14 or 28 days, micro-CT, histological, CD31 immunohistochemical, and dynamic bone histomorphometric analyses showed that DFO dramatically stimulated bone formation and angiogenesis in a critically sized osteoporotic femur defect model. Our in vitro and in vivo results demonstrate that DFO may promote the healing of osteoporotic bone defects due to enhanced angiogenesis and osteogenesis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2515-2527, 2016.